Method for Friedel-Crafts acylation of anilides

ABSTRACT

An anilide is reacted with an acylating agent by using as a catalyst a tri(perfluoroalkane sulfonate) compound of any of the elements belonging to groups 3 to 5 and groups 13 to 15 in periods 4 to 6 of the periodic table, thereby bonding an acyl group to the benzene ring. Thus, ketoaniline derivatives, which are useful as physiologically active compounds or intermediates in synthesizing the same, are synthesized in high reaction yield by catalytic acylation.

This application is a continuation application of Ser. No. 10/250,861filed Aug. 13, 2003, now abandoned, which is a 371 application ofPCT/JP02/00020 filed Jan. 8, 2002.

TECHNICAL FIELD

The present invention relates to a method for the Friedel-Craftsacylation of anilides. More specifically, the present invention relatesto a novel method of Friedel-Crafts acylation that enables the synthesisof ketoanilides useful as physiologically active compounds orintermediates for the synthesis of the same, in high reaction yieldthrough catalytic reaction.

BACKGROUND ART

Friedel-Crafts acylation has been known to be a basic and useful methodof preparing aromatic ketones. For Friedel-Crafts acylation, a catalyticamount of Lewis acid is used, while in acylation, more than astoichiometric amount of Lewis acid such as AlCl₃ is normally required.However, environmental problems that needs to be considered are evokedby the large amount of aluminum residue derived from AlCl₃, especiallyin industrial-scale processes. For solving such problems, several typesof excellent catalysts have been developed, and catalytic acylation ofactive benzenes such as anisole, xylene and toluene have been realized.However, the realization of catalytic Friedel-Crafts acylation ofbenzene and inactive benzenes such as chlorobenzene has still beendifficult. Under these circumstances, in recent years, Dubac et al. andthe present inventor's group have found and reported in the followingliterature that Bi(OTf)₃, Hf(OTf)₄ and the like are effective catalystsfor the Friedel-Crafts acylation of benzene and inactive benzenes.

TABLE 1 (a) Desmurs, J. R.; Labrouillere, M.; Roux, C. L.; Gaspard, H.;Laporterie, A.; Dubac, J. Tetrahedron Lett. 1997, 38, 8871. (b)Repichet, S.: Roux, C. L.; Dubac, J.; Desmurs, J. -R. Eur. J. Org. Chem.1998, 2743.

TABLE 2 (a) Hachiya, I.; Moriwaki, M.; Kobayashi, S. Tetrahedron Lett.1995, 36, 409. (b) Hachiya, I.; Moriwaki, M.; Kobayashi, S. Bull. Chem.Soc. Jpn. 1995, 68, 2053. (c) Kobayashi, S.; Iwamoto, S. TetrahedronLett. 1998, 39, 4697.

Further, quite recently, the present inventors have found that galliumcatalysts, especially gallium tri(perfluoroalkane sulfonate), exhibitsthe highest activity in Friedel-Crafts acylation (Matsuo, J.; Odashima,K.; Kobayashi, S. Synlett 2000, 403).

Meanwhile, it has been found that ketoaniline structures are importantin physiologically active compounds and fine chemicals, and therealization of means to efficiently synthesize these compounds whilecontrolling their structures, has become an important subject. However,while the Friedel-Crafts acylation of aniline derivatives is a simpleand clear method of introducing an acyl group into a benzene ring, andwhile a novel Friedel-Crafts acylation method for the synthesis ofaromatic ketones has been realized by the present inventor's group asstated above, actual examples of a catalytic reaction have not yet beenreported.

Accordingly, the present invention aims to provide, under the foregoingcircumstances, a novel Friedel-Crafts acylation method that enables thesynthesis of ketoaniline derivatives useful as physiologically activecompounds or intermediates thereof, in high reaction yield throughcatalytic reaction.

DISCLOSURE OF THE INVENTION

In order to solve the foregoing problems, the present invention firstlyprovides a method for Friedel-Crafts acylation of anilide, whichcomprises reacting an anilide with an acylating agent, using as acatalyst a tri(perfluoroalkane sulfonate) compound of an element thatbelongs to any one of periods 4 to 6 of the periodic table, that alsobelongs to any one of groups 3 to 5 or groups 13 to 15, thereby bondingan acyl group to a benzene ring.

Further, the present invention provides secondly, the method forFriedel-Crafts acylation of anilide, wherein the catalyst is one or moretri(perfluoroalkane sulfonate) compound(s) of an element selected fromthe group consisting of Ga, Sc, In, Y, Lanthanoids, Zr, Hf, Sn, Pb, Nb,Ta, Sb and Bi; thirdly, the method for Friedel-Crafts acylation ofanilide, wherein the reaction is performed in a nitroalkane solventcontaining a perchlorate or a halogenated hydrocarbon solvent; fourthly,the method for Friedel-Crafts acylation of anilide, wherein theperchlorate is an alkali metal perchlorate; and fifthly, the method forFriedel-Crafts acylation of anilide, wherein the acylating agent is anacid anhydride, an acid halide, an ester or a carboxylic acid.

Still further, the present invention sixthly provides the method forFriedel-Crafts acylation of anilide, wherein an anilide represented bythe following formula (1)

(wherein R¹ and R² each represent a hydrogen atom, a hydrocarbon groupthat may contain a substituent, or an acyl group represented by Ra—CO—,Ra—SO₂— or Ra—OCO—, in which Ra represents a hydrocarbon group that maycontain a substituent, at least one of R¹ and R² being theaforementioned acyl group; R³ represents a substituent bonded to thebenzene ring, and R³ may be absent) with an acylating agent representedby the following formula (2)

(wherein R⁴ represents a hydrocarbon group that may contain asubstituent; and R⁵ represents —O—CO—Rb, in which Rb is a hydrocarbongroup that may contain a substituent, a halogen atom or —OH) therebysynthesizing an acylanilide represented by the following formula (3)

(wherein R^(1,) R^(2,) R³ and R⁴ are as defined above).

The difficulty encountered in the Friedel-Crafts acylation of anilinederivatives is considered to be attributed to the decrease in activationof the Lewis acid catalyst, or rather, the deactivation of the Lewisacid catalyst, caused by the basic nitrogen of the amino group in theaniline derivatives. In fact, even in conventional reaction methods thatuse a large amount of AlCl₃, acylation barely occurs.

On the contrary, the above-described present invention dramaticallyimproves the reaction yield and facilitates the introduction of an acylgroup to anilides as aniline derivatives.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention has the foregoing characteristics, andhereinafter, embodiments are described.

In the present invention, an anilide, that is, a compound containing atleast one acyl group bonded to the amino group of aniline, is reactedwith an acylating agent to bond the acyl group to the benzene ring.

In this acylation reaction, a tri(perfluoroalkane sulfonate) compound ofan element that belongs to any one of periods 4 to 6 of the periodictable while also belonging to groups 3 to 5 or groups 13 to 15 of theperiodic table is used as a catalyst. This compound is used as a Lewisacid catalyst that is active specifically in the Friedel-Craftsacylation of the anilide. Of course, the catalyst compounds can be usedsingularly or in combination. As the element constituting such catalystcompounds, for example, Ga, Sc, In, Y, lanthanoid, Zr, Hf, Sn, Pb, Nb,Ta, Sb and Bi may be exemplified. Further, as the perfluoroalkanesulfonate, perfluoroalkane sulfonates containing about 1 to 10 carbonatoms, such as trifluoromethane sulfonate (—OTf) and nonafluorobutanesulfonate (—ONf) may be exemplified.

Of these catalyst compounds, Ga tri(perfluoroalkane sulfonates), Sctri(perfluoroalkane sulfonates), Hf tri(perfluoroalkane sulfonates). Sbtri(perfluoroalkane sulfonates) and Bi tri(perfluoroalkane sulfonates)are exemplified, and Ga tri(perfluoroalkane sulfonates) such as Ga(OTf),and Ga(ONf)₃ may be listed as catalyst compounds that are especiallyactive. Such catalyst compounds may be used in a catalytic amount;normally, an amount such as 1 to 50 mol % of the reaction substrate orpreferably, 5 to 20 mol % of the reaction substrate may be considered.

In the present invention, together with the catalyst compound, thepresence of a solvent may be considered. Although the reaction may beconducted without the use of a solvent, a nitroalkane solvent thatcontains a perchlorate or a halogenated hydrocarbon solvent ispreferably used as the solvent for the acylation of this invention.

As the nitroalkane solvent, various compounds such as nitromethane andnitroethane may be considered. These may be used either singularly or incombination. However, with nitroalkane alone, the desired reactionactivity can not be obtained. As described above, when a nitroalkanesolvent is used, it is used after adding perchlorate. This additiondramatically increases the reaction yield.

As the perchlorate, alkali metal perchlorates such as LiClO₄, KClO₄ andNaClO₄ are preferable. Of these, LiClO₄ is especially effective.

When these perchlorates are in the form of alkali metal salts, they arecommonly used as 1 to 10 M nitroalkane solutions.

As the halogenated hydrocarbon solvent, for example, 1,2-dichloroethaneand the like may be used. Regarding these halogenated hydrocarbonsolvents, an excellent effect is exhibited to provide high acylationyield, especially when acid halide is used as the acylating agent.

Regarding the anilide as the reaction substrate, the acyl group bondedto the amino group of aniline not only includes carbonyl group (—CO—),but may also include various groups such as sulfonyl group (—SO₂—) andcarbonyl group (—OCO—).

Further, as the acylating agent used in the reaction, various compoundssuch as acid anhydrides, acid halides, esters and carboxylic acids maybe used. As mentioned above, when an acid halide is used, a halogenatedhydrocarbon solvent may effectively be used. Moreover, when a carboxylicacid is used, the addition of a trifluoroacetic anhydride is effective.

Various acylanilides are synthesized in high yield by the method of thepresent invention. Specifically, for example, the acylaniliderepresented by the above formula (3) is synthesized by the reaction ofthe anilide of the above formula (1) with the acylating agent of theabove formula (2).

When R¹, R² and Ra in the anilide of formula (1) are hydrocarbon groupsthat may contain a substituent, the hydrocarbon group may be analiphatic, alicyclic or aromatic hydrocarbon group, and may containvarious substituents as long as they do not inhibit the acylationreaction. This is the same for R⁴ and Rb in formula (2) that representsthe acylating agent.

Further, R³ representing the substituent attached to the benzene ring inthe anilide of formula (1) may be absent, or it may be a substituentsuch as a hydrocarbon group or an alkoxy group, that does not inhibitthe acylation reaction. A plurality of the same type or different typesof such groups may be bonded to the benzene ring.

In the method of the present invention, the acyl group may selectivelybe bonded to the para- or meta-position of the anilide by the presenceof substituent R³ and by selecting R¹ and R².

Regarding the ratio of the anilide as the reaction substrate and theacylating agent, the anilide/acylating agent ratio, in terms of molarratio, may usually be in the range of 1/10 to 10/1, preferably 2/10 to10/5. For a nitroalkane solvent, the reaction temperature may be in therange of 5 to 60° C., and for a halogenated hydrocarbon solvent, thereaction temperature may be as high as its reflux temperature. Thereaction may be conducted in atmospheric pressure or under increasedpressure. The atmosphere may be inert gas-atmosphere such as N₂ or Ar.

Hereinafter, the present invention is described in more detail byreferring to the following Examples. Of course, the description is notlimited by the following Examples.

EXAMPLES Example 1

The Friedel-Crafts acylation of acetoanilide was conducted using a GaLewis acid catalyst according to the following reaction scheme.

The results are shown in Table 3.

As a typical example of the reaction procedure, that of entry No. 4 inTable 3 is described:

That is, to a solution obtained by stirring acetylanilide (108 mg, 0.80mmol), LiClO₄ (1.28 mg, 12.0 mmol), acetic anhydride (168 mg, 1.65 mmol)and nitromethane (2.0 mL) was added 10 mol % of Ga(OTf)₄ (41.5 mg, 0.08mmol) based on the amount of acetylanilide as the reaction substrate.The mixture was stirred at 50° C. for 24 hours, after which the reactionmixture was cooled with saturated aqueous NaHCO₃ (10 mL). The aqueouslayer was extracted with CH₃Cl₂ (3×15 mL). The combined organic layerwas dried over Na₂SO₄, and the concentrated residue was subjected tocolumn chromatography on silica gel (50/1—CHCl₃/MeOH) to obtain acolorless solid product 2a (131 mg, 93%).

TABLE 3 Entry Lewis acid Solvent (Media) Yield (%) 1 Ga(OTf)₃ CH₃NO₂ 3 2Ga(OTf)₃ MeNO₂—LiClO₄ (3 M) 62 3 Ga(OTf)₃ MeNO₂—LiClO₄ (4.8 M) 82 4Ga(OTf)₃ MeNO₂—LiClO₄ (6 M) 93 5 Ga(ONf)₃ MeNO₂—LiClO₄ (6 M) 90 6 GaCl₃MeNO₂—LiClO₄ (6 M) 33

From Table 3, it was found that in the reaction of acetoanilide (1a)with acetic anhydride using 10 mol % of Ga(OTf)₃, Ga(OTf)₃ in itselfshows extremely low reaction activity in nitromethane (MeNO₂) as shownin Entry No. 1, whereas the addition of lithium perchlorate (LiClO₄)dramatically increases the reaction yield. As the amount of LiClO₄increased, the yield of fraction product 2a increased; the acetylationproduct 2a was obtained in a yield of 93% in a 6.0 M MeNO₂—LiClO₄solution, as shown in Entry No. 4.

As shown in Entry No. 5, it was verified that galliumtri(nonafluorobutane sulfonate) (Ga(ONf)₃) also acts as an effectivecatalyst. However, the catalytic activity of GaCl₃ was low.

Incidentally, the identification results of the above-describedacylation product 2a were as follows:

TABLE 4 2a: Mp 169–171° C. ¹H NMR(CDCl₃) δ 2.22(s, 3H), 2.58(s, 3H),7.63(d, J=8.8Hz, 2H), 7.75(brs, 1H), 7.94(d, J=8.8Hz, 2H): ¹³CNMR(CDCl₃) δ 24.81 26.48, 118.85, 129.76, 132.80, 142.35, 168.68,197.11.

Example 2

The acylation reaction was conducted in the manner described in Example1 using other catalysts such as Sc(OTf)₃, Sc(ONf)₃, Hf(OTf)₃, Sb(OTf)₃and Bi(OTf)₃. The results are shown in Table 5. The same acetylationproduct 2a was obtained.

Here, AlCl₃, a typical Lewis acid for Friedel-Crafts acylation used as aComparative Example was not effective. In a MeNO₂—LiClO₄ solution, evenAlCl₃ of more than a stoichiometric amount barely showed reactionactivity. In addition, when the reaction was performed using aceticanhydride in 1,2-dichloroethane in the presence of 3.2 equivalents ofAlCl₃ at 50° C. for 12 hours, an acetylation product was obtained at ayield of 9%.

TABLE 5 Lewis acid Solvent (Media) Yield (%) Sc(OTf)₃ MeNO₂—LiClO₄ (6 M)10 Sc(ONf)₃ MeNO₂—LiClO₄ (6 M) 48 Hf(OTf)₄ MeNO₂—LiClO₄ (6 M) 44Sb(OTf)₃ MeNO₂—LiClO₄ (6 M) 59 Bi(OTf)₃ MeNO₂—LiClO₄ (6 M) 59 AlCl₃ ^(a)MeNO₂—LiClO₄ (6 M) <1 none MeNO₂—LiClO₄ (6 M) <1 AlCl₃ ^(b) ClCH₂CH₂Cl 9^(a)AlCl₃ (5.1 equiv) was used. ^(b)AlCl₃ (3.2 equiv) was used. Thereaction time was 12 h.

Example 3

The acylation reaction was conducted as described in Example 1 usingvarious anilides and acylating agents. Ga(OTf)₃ and Ga(ONf)₃ were usedas the catalyst. The results are shown in Table 6.

TABLE 6

Entry Lewis acid R¹ R² R³ R⁴ R⁵ Product Yield (%) 1 Ga(OTf)₃ Ac H H (1a)Me OAc 2a 93 2 Ga(OTf)₃ Bz H H (1b) Me OAc 2b quant 3 Ga(OTf)₃ Bz H H(1b) Et OCOEt 2c 95 4 Ga(OTf)₃ Bz H H (1b) i-Pr OCOi-Pr 2d 74 (83)^(a) 5Ga(OTf)₃ Ms Me H (1c) Me OAc 2e 97 6 Ga(OTf)₃ Ac H o-Me (1d) Me OAc 2f61^(a) 7 Ga(OTf)₃ Ac H o-OMe (1e) Me OAc 2g 75^(a,b) 8 Ga(ONf)₃ Ms Meo-OMe (1f) Me OAc 2h 79 9 Ga(OTf)₃ Ac H m-Me (1g) Me OAc 2i 62 10Ga(ONf)₃ Ms Me m-Me (1h) Me OAc 2j 62 11 Ga(ONf)₃ Ms Me m-OMe (1i) MeOAc 2k 78 12 Ga(OTf)₃ MS Me p-OMe (1j) Me OAc 2l 54^(a) 13 Ga(OTf)₃ MsMe H (1c) Ph Cl 2m quant^(c,d) 14 Ga(ONf)₃ i-BuOCO H H (1k) Ph Cl 2n80^(c) 15 Ga(OTf)₃ Bz H H (1b) Me OH 2b 90^(a) ^(a)Twenty mol % at thecatalyst was used. ^(b)Regioisomer 2g′ was obtained in 5% yield. ^(c)Thereaction was carried out in 1,2-dichloromethane under reflux for 24 h.^(d)After the acylation, the crude product was treated with 25%HBr/AcOH. ^(e)Trifiuoroacetic anhydride was added.

In this Table 6, reaction products 2a, 2b, 2c, 2d, 2e, 2f, 2i, 2j and 2kwere all products in which the acyl group R⁴—CO— is bonded to thep-(para) position of the benzene ring. Meanwhile, reaction product 2gwas obtained as a mixture with 2g′ as shown below.

Further, reaction products 2h and 2l indicate the following products.

In all entries, the reaction proceeded smoothly in the presence of acatalytic amount of the gallium compound in MeNO₂—LiClO₄ and showedexcellent yield. Acetoanilide (1a), a well as benzanilide (1b) reactedwith certain acetic anhydrides to obtain the corresponding acylationproduct in high yield.

Further, N-methanesulfonyl (MS)-N-methylaniline (1c) was reacted withacetic anhydride in the presence of 10 mol % of Ga(OTf)₃ to obtainacylation product 2e in a 97% yield. Some o- and m-substituted anilinederivatives also provided acylation products in high yield in thepresence of a catalytic amount of Ga(OTf)₃ or G(ONf)₃.

In the benzoylation reaction, 1c and 1k reacted smoothly with benzoylchloride in 1,2-dichloroethane under reflux for 24 hours to give thedesired products (2m and 2n) in high yield. When carboxylic acid wasused as the acylating agent, the desired acylation product (2b) wasobtained in excellent yield without the formation of atrifluoroacetylation adduct, by adding trifluoroacetic anhydride.

Identification results for compounds 2b to 2n as the reaction productswere as shown in Tables 7, 8 and 9.

TABLE 7 2b: ¹H NMR(CDCl₃) δ 2.60(s, 3H), 2.58(s, 3H), 7.26–8.02(m, 10H);¹³C NMR(CDCl₃) δ 26.48, 119.24, 127.07, 128.97, 129.85, 132.31, 133.17,134.48, 142.26, 165.75, 196.90. Zc: Mp 189–191° C.(lit² 187–188° C.). ¹HNMR(CDCl₃) δ 1.23(t, J=7.3Hz, 3H), 2.99(q, J=7.3Hz, 2H), 7.49(t,J=7.3Hz, 2H), 7.58(t, J=7.3Hz. 1H), 7.76(d, J=8.7Hz, 1H), 7.88(d,J=7.3Hz, 1H), 7.99(d, J=8.7Hz, 1H), 8.06–8.14(bs, 1H): ¹³C NMR(CDCl₃) δ8.3, 31.6, 119.3, 127.1, 128.9, 129.4, 132.2, 132.9, 134.5, 142.1,165.8, 199.7. 2d: ¹H NMR(CDCl₃) δ 1.16(d, J=6.6Hz, 6H), δ 3.50(m, 1H),7.25–7.50(m, 3H), 7.80–7.93(6s, 6H), 9.30–9.48(m, 1H): ¹³C NMR(CDCl₃) δ18.99, 19.22, 34.88, 119.70, 127.18, 128.35, 129.34, 131.39, 131.79,134.21, 142.56, 166.60, 203.70. 2e: ¹H NMR(CDCl₃) δ 2.61(s, 3H), 2.87(s,3H), 3.38(s, 3H), 7.49(d, J=8.8Hz, 2H), 7.99(d, J=8.8Hz, 2H); ¹³CNMR(CDCl₃) δ 26.64, 35.79, 37.56, 124.67, 129.49, 135.13, 145.53,196.92, MS(EI) m/z 227(M⁺) 2f: Mp 142–144° C.(lit.³ 141–142° C.), ¹HNMR(CDCl₃) δ 2.24(s, 3H), 2.32(s, 3H), 2.57(s, 3H), 7, 12–7.22(bs, 1H),7.78–7.83(m, 2H), 8.10–8.19(m, 1H); ¹³C NMR(CDCl₃) δ 17.6, 17.7, 24.4,36.36, 26.38, 121.6, 127.5, 130.4, 133.1, 140.4, 168.6, 197.4.

TABLE 8 2g: Mp 119–120° C.(lit.⁴ 122.5° C.), ¹H NMR(CDCl₃) δ 2.23(s,3H), 2.58(s, 3H), 3.95(s, 3H). 6.93(d, J=8.6Hz. 1H), 7.74(dd, J=8.6,22Hz. 1H), 8.99(d, J=2.2Hz, 1H); ¹³C NMR(CDCl₃) δ 24.9, 26.5, 56.0,109.5, 120.4, 124.4, 127.4, 130.5, 151.2, 168.3, 197.2. 2h: Mp 125–127°C. ¹H NMR(CDCl₃) δ 2.57(s, 3H), 2.97(s, 3H), 3.27(s, 3H), 3.98(s, 3H).7.00(d. J=8.4Hz. 1H), 7.97(d, J=2.2Hz. 1H), 7.99(dd, J=8.4, 2,2Hz. 1H);¹³C NMR(CDCl₃) δ 26.4, 37.6, 38.2, 56.0, 111.7, 129.1, 130.4, 130.9,132.9, 159.9, 196.0 2i: Mp 131–133° C.(lit.⁵ 135–136° C.), ¹H NMR(CDCl₃)δ 2.20(s, 3H), 2.51(s, 3H), 2.56(s, 3H), 7.32(s, 1H), 7.57(d, J=8.4Hz.1H), 7.71(d, J=8.4Hz. 1H), 8.08–8.18(bs, 1H); ¹³C NMR(CDCl₃) δ 22.1,24.6, 29.2, 116.3, 122.3, 131.4, 132.7, 140.6, 141.0, 168.9, 200.3. 2j:Mp 111–114° C. ¹H NMR(CDCl₃) δ 2.55(s, 314), 2.58(s, 3H), δ 2.87(s, 3H).3.35(s, 3H). 7.24(d, J=2.3Hz. 1H), 7.31(dd, J=8.4, 2.3Hz, 1H), 7.73(d,J=8.4Hz. 1H); ¹³C NMR(CDCl₃) δ 21.8, 29.5, 35.8, 37.6, 122.2, 128.0,130.5, 135.8, 140.2, 143.9, 200.4. 2k: Mp 83–85° C. ¹H NMR(CDCl₃) δ2.62(s, 3H), 2.86(s, 3H), 3.35(s, 3H), 3.94(s, 3H), 6.92(dd, J=8.5,2.0Hz. 1H), 7.13(d, J=2.0Hz. 1H), 7.78(d, J=8.5Hz, 1H); ¹³C NMR(CDCl₃) δ31.8, 35.5, 37.6, 55.8, 110.1, 115.1, 126.5, 131.3, 146.2, 159.4, 198.5.

TABLE 9 2l: Mp 112–114° C. ¹H NMR(CDCl₃) δ 2.63(s, 3H), 2.84(s, 3H),3.30(s, 3H), 3.94(s, 3H). 7.00(d, J=5.5Hz, 1H), 7.56(dd, J=5.5, 1.8Hz.1H), 7.70(d, J=1.8Hz. 1H); ¹³C NMR(CDCl₃) δ 31.8, 35.1, 38.2, 55.9,112.6, 126.8, 128.2, 133.8, 134.2, 158.2, 198.5. 2m: ¹H NMR(CDCl₃) δ2.99(d, J=5.1Hz. 3H), 4.88–4.95(bs, 1H), 7.41–7.58(m, 3H), 7.66 7.77(m,J=8.6, 4H), 8.02(d, J=2.0Hz, 1H); ¹³C NMR(CDCl₃) δ 30.3, 108.8, 109.0.126.7, 128.2, 129.4, 131.5, 132.1, 135.0, 138.6, 149.3, 194.0. 2n: ¹HNMR(CDCl₃) δ 0.98(d, J=6.8Hz. 6H), 2.00(d, J=6.8Hz. 1H), 3.99(d,J=6.8Hz. 2H), 6.84–6.87(bs. 1H), 7.44–7.61(m, 5H), 7.74–7.85(m, 4H); ¹³CNMR(CDCl₃) δ 19.0. 27.9, 71.7, 113.6, 117.5, 128.2, 129.8, 131.7, 132.1,137.9, 142.2, 153.3, 195.6.

INDUSTRIAL APPLICABILITY

As has been described in detail above, according to the presentinvention, a Friedel-Crafts acylation method that enables the synthesisof ketoaniline derivatives useful as physiologically active compounds orintermediates for the synthesis of the same, in high reaction yield bycatalytic acylation is provided.

1. A method for Friedel-Crafts acylation of anilide, which comprisesreacting an anilide with an acylating agent in the presence of aperchlorate, using as a catalyst a tri(perfluoroalkane sulfonate)compound of an element selected from the group consisting of Ga, Sb andBi, thereby bonding an acyl group to a benzene ring.
 2. The method forFriedel-Crafts acylation of anilide of claim 1, wherein the reaction isperformed in a nitroalkane solvent or a halogenated hydrocarbon solvent.3. The method for Friedel-Crafts acylation of anilide of claim 1,wherein the perchiorate is an alkali metal perchlorate.
 4. The methodfor Friedel-Crafts acylation of anilide of claim 2, wherein theperchlorate is an alkali metal perchlorate.
 5. The method forFriedel-Crafts acylation of anilide of claim 1, wherein the acylatingagent is an acid anhydride, an acid halide, an ester or a carboxylicacid.
 6. The method for Friedel-Crafts acylation of anilide of claim 2,wherein the acylating agent is an acid anhydride, an acid halide, anester or a carboxylic acid.
 7. The method for Friedel-Crafts acylationof anilide of claim 3, wherein the acylating agent is an acid anhydride,an acid halide, an ester or a carboxylic acid.
 8. The method forFriedel-Crafts acylation of anilide of claim 4, wherein the acylatingagent is an acid anhydride, an acid halide, an ester or a carboxylicacid.
 9. The method for Friedel-Crafts acylation of anilide of claim 1,wherein an anilide represented by the following formula (1)

wherein R¹ and R² each represent a hydrogen atom, a hydrocarbon groupthat may contain a substituent, or an acyl group represented by Ra—CO—,Ra—SO₂— or Ra—OCO—, in which Ra represents a hydrocarbon group that maycontain a substituent, at least one of R¹ and R² being the acyl group;and R³ represents a substituent bonded to the benzene ring, and R³ maybe absent, is reacted with an acylating agent represented by thefollowing formula (2)

wherein R⁴ represents a hydrocarbon group that may contain asubstituent; and R⁵ represents —O—CO—Rb, in which Rb is a hydrocarbongroup that may contain a substituent, a halogen atom or —OH, therebysynthesizing an acylanilide represented by the following formula (3)

 wherein R¹, R^(2,) R³ and R⁴ are as defined above.
 10. The method forFriedel-Crafts acylation of anilide of claim 2, wherein an aniliderepresented by the following formula (1)

wherein R¹ and R² each represent a hydrogen atom, a hydrocarbon groupthat may contain a substituent, or an acyl group represented by Ra—CO—,Ra—SO₂— or Ra—OCO—, in which Ra represents a hydrocarbon group that maycontain a substituent, at least one of R¹ and R² being the acyl group;and R³ represents a substituent bonded to the benzene ring, and R³ maybe absent, is reacted with an acylating agent represented by thefollowing formula (2)

wherein R⁴ represents a hydrocarbon group that may contain asubstituent; and R⁵ represents —O—CO—Rb, in which Rb is a hydrocarbongroup that may contain a substituent, a halogen atom or —OH, therebysynthesizing an acylanilide represented by the following formula (3)

 wherein R¹, R², R³ and R⁴ are as defined above.
 11. The method forFriedel-Crafts acylation of anilide of claim 3, wherein an aniliderepresented by the following formula (1)

wherein R¹ and R² each represent a hydrogen atom, a hydrocarbon groupthat may contain a substituent, or an acyl group represented by Ra—CO—,Ra—SO₂— or Ra—OCO—, in which Ra represents a hydrocarbon group that maycontain a substituent, at least one of R¹ and R² being the acyl group;and R³ represents a substituent bonded to the benzene ring, and R³ maybe absent, is reacted with an acylating agent represented by thefollowing formula (2)

wherein R⁴ represents a hydrocarbon group that may contain asubstituent; and R⁵ represents —O—CO—Rb, in which Rb is a hydrocarbongroup that may contain a substituent, a halogen atom or —OH, therebysynthesizing an acylanilide represented by the following formula (3)

 wherein R¹, R², R³ and R⁴ are as defined above.
 12. The method forFriedel-Crafts acylation of anilide of claim 4, wherein an aniliderepresented by the following formula (1)

wherein R¹ and R² each represent a hydrogen atom, a hydrocarbon groupthat may contain a substituent, or an acyl group represented by Ra—CO—,Ra—SO²— or Ra—OCO—, in which Ra represents a hydrocarbon group that maycontain a substituent, at least one of R¹ and R² being the acyl group;and R³ represents a substituent bonded to the benzene ring, and R³ maybe absent, is reacted with an acylating agent represented by thefollowing formula (2)

wherein R⁴ represents a hydrocarbon group that may contain asubstituent; and R⁵ represents —O—CO—Rb, in which Rb is a hydrocarbongroup that may contain a substituent, a halogen atom or —OH, therebysynthesizing an acylanilide represented by the following formula (3)

 wherein R¹, R², R³ and R⁴ are as defined above.
 13. The method forFriedel-Crafts acylation of anilide of claim 5, wherein an aniliderepresented by the following formula (1)

wherein R¹ and R² each represent a hydrogen atom, a hydrocarbon groupthat may contain a substituent, or an acyl group represented by Ra—CO—,Ra—SO₂— or Ra—OCO—, in which Ra represents a hydrocarbon group that maycontain a substituent, at least one of R¹ and R² being the acyl group;and R³ represents a substituent bonded to the benzene ring, and R³ maybe absent, is reacted with an acylating agent represented by thefollowing formula (2)

wherein R⁴ represents a hydrocarbon group that may contain asubstituent; and R⁵ represents —O—CO—Rb, in which Rb is a hydrocarbongroup that may contain a substituent, a halogen atom or —OH, therebysynthesizing an acylanilide represented by the following formula (3)

 wherein R¹, R², R³ and R⁴ are as defined above.
 14. The method forFriedel-Crafts acylation of anilide of claim 6, wherein an aniliderepresented by the following formula (1)

wherein R¹ and R² each represent a hydrogen atom, a hydrocarbon groupthat may contain a substituent, or an acyl group represented by Ra—CO—,Ra—SO₂— or Ra—OCO—, in which Ra represents a hydrocarbon group that maycontain a substituent, at least one of R¹ and R² being the acyl group;and R³ represents a substituent bonded to the benzene ring, and R³ maybe absent, is reacted with an acylating agent represented by thefollowing formula (2)

wherein R⁴ represents a hydrocarbon group that may contain asubstituent; and R⁵ represents —O—CO—Rb, in which Rb is a hydrocarbongroup that may contain a substituent, a halogen atom or —OH, therebysynthesizing an acylanilide represented by the following formula (3)

 wherein R¹, R², R³ and R⁴ are as defined above.
 15. The method forFriedel-Crafts acylation of anilide of claim 7, wherein an aniliderepresented by the following formula (1)

wherein R¹ and R² each represent a hydrogen atom, a hydrocarbon groupthat may contain a substituent, or an acyl group represented by Ra—CO—,Ra—SO₂— or Ra—OCO—, in which Ra represents a hydrocarbon group that maycontain a substituent, at least one of R¹ and R² being the acyl group;and R³ represents a substituent bonded to the benzene ring, and R³ maybe absent, is reacted with an acylating agent represented by thefollowing formula (2)

wherein R⁴ represents a hydrocarbon group that may contain asubstituent; and R⁵ represents —O—CO—Rb, in which Rb is a hydrocarbongroup that may contain a substituent, a halogen atom or —OH, therebysynthesizing an acylanilide represented by the following formula (3)

 wherein R¹, R², R³ and R⁴ are as defined above.
 16. The method forFriedel-Crafts acylation of anilide of claim 8, wherein an aniliderepresented by the following formula (1)

wherein R¹ and R² each represent a hydrogen atom, a hydrocarbon groupthat may contain a substituent, or an acyl group represented by Ra—CO—,Ra—SO₂— or Ra—OCO—, in which Ra represents a hydrocarbon group that maycontain a substituent, at least one of R¹ and R² being the acyl group;and R³ represents a substituent bonded to the benzene ring, and R³ maybe absent, is reacted with an acylating agent represented by thefollowing formula (2)

wherein R⁴ represents a hydrocarbon group that may contain asubstituent; and R⁵ represents —O—CO—Rb, in which Rb is a hydrocarbongroup that may contain a substituent, a halogen atom or —OH, therebysynthesizing an acylanilide represented by the following formula (3)

 wherein R¹, R², R³ and R⁴ are as defined above.